Hypersensitive glutamate signaling correlates with the development of late-onset behavioral morbidity in diffuse brain-injured circuitry

J Neurotrauma. 2012 Jan 20;29(2):187-200. doi: 10.1089/neu.2011.2091. Epub 2011 Dec 1.


In diffuse brain-injured rats, robust sensory sensitivity to manual whisker stimulation develops over 1 month post-injury, comparable to agitation expressed by brain-injured individuals with overstimulation. In the rat, whisker somatosensation relies on thalamocortical glutamatergic relays between the ventral posterior medial (VPM) thalamus and barrel fields of somatosensory cortex (S1BF). Using novel glutamate-selective microelectrode arrays coupled to amperometry, we test the hypothesis that disrupted glutamatergic neurotransmission underlies the whisker sensory sensitivity associated with diffuse brain injury. We report hypersensitive glutamate neurotransmission that parallels and correlates with the development of post-traumatic sensory sensitivity. Hypersensitivity is demonstrated by significant 110% increases in VPM extracellular glutamate levels, and 100% increase in potassium-evoked glutamate release in the VPM and S1BF, with no change in glutamate clearance. Further, evoked glutamate release showed 50% greater sensitivity to a calcium channel antagonist in brain-injured over uninjured VPM. In conjunction with no changes in glutamate transporter gene expression and exogenous glutamate clearance efficiency, these data support a presynaptic origin for enduring post-traumatic circuit alterations. In the anatomically-distinct whisker circuit, the injury-induced functional alterations correlate with the development of late-onset behavioral morbidity. Effective therapies to modulate presynaptic glutamate function in diffuse-injured circuits may translate into improvements in essential brain function and behavioral performance in other brain-injured circuits in rodents and in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Afferent Pathways / physiology*
  • Afferent Pathways / physiopathology
  • Animals
  • Behavior, Animal / physiology*
  • Brain Injuries / metabolism
  • Brain Injuries / physiopathology
  • Diffuse Axonal Injury / metabolism*
  • Diffuse Axonal Injury / physiopathology
  • Disease Models, Animal
  • Glutamic Acid / physiology*
  • Hyperesthesia / metabolism*
  • Hyperesthesia / physiopathology
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / physiology*
  • Time Factors


  • Glutamic Acid